Periodic Reporting for period 1 - DYNAMICE (DYNAMICE: An integrated framework for biomechanical phenotyping of arteries to disentangle mechanical causes of arterial stiffening in diabetes)
Reporting period: 2019-04-01 to 2021-03-31
Being a Marie Curie Global Fellowship, this fellowship consists of two periods: 1) an outgoing phase at Yale University (United States), and 2) a return-to-the-EU phase at Maastricht University (the Netherlands). This report pertains to period #1, as period #2 is still in progress.
While working on these projects, we implemented from scratch a thick-walled, bi-layered model of arterial wall mechanics, including an explicit model of active smooth muscle contraction. This was extended into a growth and remodelling formulation, where such smooth muscle contraction modulates arterial tone and in turn influences arterial remodelling and inflammation.
In parallel, through collaboration with Maastricht University, we studied the effects of the diabetes-related crosslinking effects of methylglyoxal (MGO), one of the most potent AGE precursors, in multiple studies. First, we performed a literature review and found that in the current literature, there is no direct evidence to date of an association between MGO or MGO-derived advanced glycation end-products, and arterial stiffening. Second, in a preclinical study, we investigated how oral MGO supplementation influenced arterial stiffness. Third, we tested how direct incubation of an artery in a high-concentration MGO solution alters its mechanics. Fourth, in a clinical cross-sectional cohort study, we assessed whether there was an association between plasma MGO concentration and arterial stiffness. Finally, in a clinical study, we assessed whether pyridoxamine, an AGE inhibitor, attenuated arterial stiffening. We did not observe such effect.
At Maastricht University, we also preclinically studied the effects of arterial calcification on arterial stiffness by comparing groups subjected to different durations of warfarin treatment (inducing calcification). We are currently working on modelling these results. Finally, we developed a methodology to reliably quantify the vascular smooth muscle cell density in the arterial wall, based on two-photon laser scanning microscopy.
The knowledge gained from in vitro biomechanical experimentation can also be used for better patient diagnosis using in vivo biomechanical measurements. By using the same, consistent methodology to study biomechanical phenotypes in many preclinical models, we will build a ‘dictionary’ or ‘atlas’ of biomechanical disease signatures. Such a dictionary can subsequently be used to ‘look up’ in vivo biomechanics data and potentially diagnose disease. This approach reinforces the importance of our pulsatile way of measurement: by capturing and characterising biomechanics under in vivo-like conditions, the resulting data can be directly used as a comparator for (true) in vivo data.